In this award application we outline a strategy to identify genes that regulate cancer cell invasion, an early step in cancer metastasis, using the zebrafish. We have shown that zebrafish meltdown (mlt) mutants develop a cancer-like phenotype as a result of stromal invasion of posterior intestinal epithelial cells, mlt mutants ectopically express zebrafish orthologs of human genes strongly implicated in cancer progression. Importantly, inhibition of these genes rescues the invasive mlt phenotype. Positional cloning identified zebrafish smooth muscle myosin heavy chain (MYH11) as the responsible mlt gene. Human MYH11 has also been shown to be part of a gene expression signature that is predictive of tumor metastasis. Together, these findings support mlt as an invasive cancer model. Here, we propose experiments that will allow the identification of mlt modifier genes. The human orthologs of such genes are predicted to play a role in cancer invasion and metastasis, and may be targets for anti-cancer therapy. Three interrelated sets of experiments have been designed to identify mlt modifiers. First, we will analyze in mlt mutants the expression arid function of zebrafish orthologs of human genes with an established role in cancer cell invasion. Second, we will compare transcriptional profiles of mlt and sibling wild type larvae and assess the role of differentially expressed genes using antisense knockdown and forced expression experiments. Third, we will conduct a chemical mutagenesis genetic screen to identify recessive and dominant modifiers of the mlt cancer-like phenotype. Together, these aims provide a novel approach to identify genes that regulate human cancer progression. Functional assessment of these genes in mlt mutants provides a rapid, in vivo assay of their suitability for pharmacological targeting.